The elevation of growth hormone (GH) levels in animals, e.g., mammals including humans, upon administration of GH-releasing compounds can lead to enhanced body weight and to enhanced milk production if sufficiently elevated GH levels occur upon administration. Further, it is known that the elevation of growth hormone levels in mammals and humans can be accomplished by application of known growth hormone releasing agents, such as the naturally occurring growth hormone releasing hormones.
The elevation of growth hormone levels in mammals can also be accomplished by application of growth hormone releasing peptides (GHRPs), some of which have been previously described, for example, in U.S. Pat. Nos. 4,223,019; 4,223,020; 4,223,021; 4,224,316; 4,226,857; 4,228,155; 4,228,156; 4,228,157; 4,228,158; 4,410,512; 4,410,513.
Antibodies to the endogenous growth hormone release inhibitor, somatostatin (SRIF) have also been used to cause elevated GH levels. In this latter example, growth hormone levels are elevated by removing the endogenous GH-release inhibitor (SRIF) before it reaches the pituitary, where it inhibits the release of GH.
These methods for promoting the elevation of growth hormone levels frequently involve materials which are expensive to synthesize and/or difficult to isolate in sufficient purity for administration to a target animal. Low molecular weight, relatively simple and inexpensive compounds that have the ability to promote the release of growth hormone would be desirable in that they could be readily and inexpensively prepared, easily modified chemically and/or physically, as well as easily purified and formulated, and designed to have improved transport properties.
GH and/or GHRPs have been administered to stimulate growth hormone production and/or release, for example, to stimulate growth, enhance milk production, enhance body weight, increase rate of protein synthesis, reduce rate of carbohydrate utilization, increase mobilization of pre-fatty acids. Although the use of many of these compounds such as a series of short peptides (e.g., U.S. Pat. Nos. 5,663,146 and 5,486,505) have been important steps in the design and delivery of compounds having GH and/or GHRP properties, improvements can still be made. For example, improvements can be made in the areas of oral bioavailability, serum retention time, etc.
Non-peptidal or hybrid-peptidal secretagogues have also been described. See U.S. Pat. Nos. 5,494,919; 5,492,920; 5,492,916; 5,622,973; WO95/13069, WO96/15148; WO96/35713; WO97/22367; WO97/00894; WO97/07117; and WO97/11697. Despite the general descriptions of such compounds, it is not possible to make broad generalizations about which particular compounds are favorable. Although some secretagogues, which can promote the release and elevation of growth hormone levels in the blood, have been described, corresponding data on the biological activity has often been lacking. Moreover, even in terms of tripeptides with or without C-terminal modifications, the data suggests that it has heretofore been impossible to make the broad sweeping generalization made in those publications about what would or would not be a favorable amino acid combination at the three positions of a tripeptide holding the C-terminal constant or holding the peptidal portion constant while making changes, or changing the chemical moieties added. Changes in any of the constituents can have great effects on activity. It is submitted that these references do not lead to general teachings of biological efficacy.
In order to maximize the ability to select and tailor a compound, it would be desirable to have a class of compounds that generally provide good growth hormone releasing effects and have at least one other desirable biological activity such as better bioavailability, absorption, metabolism, pharmacokinetics, excretions, etc. It would also be desirable to have compounds which can promote the release and elevation of growth hormone levels in the blood of animals, particularly in humans, to be able to use such compounds to promote the release and/or elevation of growth hormone levels in the blood of animals and humans, and to provide methods for promoting the release and/or elevation of growth hormone levels in the blood of animals using such compounds.
The aforementioned discussion illustrates that a broad chemical diversity of synthetic GHRPs ranging from peptides to partial peptides to non-peptides. Overall, the peptides and partial peptides have been the most effective in promoting elevated growth hormone levels. For example, partial peptides consisting of natural and unnatural amino acids of different chain lengths and C-terminal amide groups or a substituted amide with various organic chemical groups. Results published as early as 1982 stated that certain GHRPs with only 3-7 amino acids released GH and that having a D-amino acid at certain positions was useful. From 1982 to the present, GHRPs with more potent GH releasing activity have been developed. This research taught that certain amino acid positions could have certain substitutions but not others, and that one amino acid residue could affect what other substitutions could be made.
Until compounds having the optimum physical-chemical properties and physiological-biological actions and effects are discovered for various diagnostic and therapeutic uses in humans, it is important to discover a general chemical approach that will result in new types of GHRPs. Such a broader GHRP chemical base will make it possible to better implement and refine the GHRP approach.
Properties of GHRPs that are important include that they are effective when administered orally. In addition, the compound should augment the normal pulsatile physiological secretion of GH. In some subjects with decreased GH secretion, GH can be replaced in a physiological way. Physiological replacement of a hormonal deficiency improves health while minimizing the potential adverse action of the hormone. This is especially important in treating older men and women, as they may be particularly susceptible to the adverse effects of over-treatment with GH. Already, chronic administration of GHRPs to animals and humans has produced anabolic effects. Body weight gain has been increased in rats, milk production has been increased in cows. Additionally, when a compound such as DAla-DβNal-Ala-Trp-DPhe-Lys-NH2 (GHRP-2) was administered to short-statured children with various degrees of GH deficiency 2-3 times per day over a 2 year period, the rate of height velocity has been accelerated in those children.
In principle, the anabolic biological effects of GHRPs emphasize the potential clinical value of the GHRP approach. The finding that GHRP-2 is less effective on height velocity than usually obtained with chronic recombinant human growth hormone (rhGH) administration, underscores the desirability for improving the GHRP approach. This includes further optimization and extension of the range of the GHRP chemistry in order to produce more effective biological actions.
In looking at these compounds, one looks at a varied series of biological effects such as the duration of action of GHRP. Other parameters that may substantially be affected by the chemistry of the GHRP include desensitization of the GHRP GH response, actions on the hypothalamus, effects on SRIF release and action, effects on ACTH and PRL release as well as possible effects on putative subclasses of GHRP receptors. All of these actions are directly and/or indirectly dependent on the GHRP chemistry, pattern and efficiency of oral absorption as well as the metabolism and secretion of the particular GHRP.